Team leader: Dr. Frederique Magdinier, DR1 INSERM (Lab director)

Associate team leader: Pr. Patrice Roll, PU-PH; AMU-AP-HM (Head of the Cell Biology Dpt, La Timone)

 

Structuration, strategy and scientific objectives

By taking advantage of a wide range of expertise and technical skills with pre-clinical in vitro and in vivo models, we propose to:

o Investigate the molecular cause and molecular mechanisms of selected rare diseases; in particular diseases characterized by epigenetic alterations;

o Identify potential druggable pathways and therapeutic targets;

o Ameliorate healthcare for patient suffering of rare genetic diseases;

 

The cell nucleus encloses, organizes and protects the genome, structured as chromatin which architecture is dynamically regulated depending on its activity during the cell cycle or differentiation processes. The shape of the nucleus and its mechanical stability are dependent on both the rigidity provided by the chromatin and the interactions of the nuclear membrane and nuclear membrane spanning proteins with the nuclear lamina and the cytoskeleton. The contractile state of cells like vascular smooth muscle cells (VSMCs) or skeletal muscle cells (SkMCs), impacts mechanically on the nucleus. Thereby, nuclear structure adapts to cell shape by still partially uncharacterized mechanisms that contribute to the organization of chromatin within the nuclear space and to its regulation.

 

Nuclear proteins such as Lamins and associated proteins regulate chromatin and epigenetic marks by modulating and maintaining heterochromatin and chromosomal domains through interactions with transcription factors and chromatin binding proteins. In response to external cues, including mechanical transduction, this “chromatin-nuclear membrane-cytoskeleton” backbone participates in most DNA transactions such as DNA replication, transcription or response to DNA damage.

 

Alterations in chromatin organization as well as modifications of the nuclear shape are hallmarks of many pathologies including several rare genetic diseases such as FacioScapuloHumeral dystrophy (FSHD) or premature ageing syndromes (PAS).

 

Through the exploration of patient’s samples together with the development of in vitro and in vivo models, our projects will address fundamental questions aimed at understanding the chromatin-nucleus-cytoskeleton interplay, identifying key actors involved in this dynamic and the cross-talks between chromatin organization, nuclear structure in rare genetic diseases.

 

Our project is divided along two main axes:

 

Axis 1: delineate the molecular causes and molecular mechanisms of selected rare diseases, by focusing on epigenetic alterations.

 

Axis 2: identify pathways underlying dysregulated chromatin-nucleus-cytoskeleton interplay in cells undergoing mechanical stress.

 

The team is organized in a cohesive manner so that expertise, technologies and resources can be shared and efficiently mobilized.

 



Projects

Principal investigators: Patrice Roll, Elise Kaspi, Diane Frankel

 

In Human, the protein-coding sequences represent only ∼2% of the genome, which is very low regarding the complexity of the organism. Besides mRNAs, many transcripts called non-coding RNAs (ncRNAs) do not encode proteins but are functional. Among ncRNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have become in recent years a new source of interest for the scientific community, allowing a better understanding of their mechanistic insights and biological functions. By regulating the expression of many target genes, miRNAs (small ncRNAs ∼20 nucleotides long) are considered as key actors in the pathophysiology of many human diseases and had become new therapeutic targets by mimic or antimiR approaches. lncRNAs (ncRNAs longer than 200 nucleotides) regulate gene expression at multiple levels: by interacting with DNA, RNA and proteins, they can modulate chromatin structure or affect RNA splicing, stability and translation. Some lncRNAs bearing miRNA-complementary sites can regulate gene expression as competitive endogenous RNAs or ‘sponges’ of miRNAs. Among the multiple molecular mechanisms which may contribute to aging modulation, miRNAs and lncRNAs are raising enormous interest due to their ability to influence several hallmarks of aging at the epigenetic level. In premature aging syndromes, few studies have focused on the role of ncRNAs, exclusively centered on miRNAs including as a therapeutic strategy to alleviate premature senescence and to increase longevity.

 

Over the last few years, our team has developed a new research axis supported by the AFM-Telethon, to evaluate the role of ncRNAs in HGPS and related progeroid syndromes. We have shown that the overexpression of miR-376a-3p and miR-376b-3p due to chromatin remodeling of the 14q32 locus, contributes to progerin accumulation by inhibiting autophagy level and leading to premature cellular senescence. Recently, we identified several other ncRNA candidates based on studies of patients’ fibroblasts and vascular smooth muscle cells (VSMCs) from LmnaG609G/G609G KI mice. In particular, we focused our attention on two miRNAs and several lncRNAs because of potential link between any of their targets and clinical disorders observed in these syndromes. We use the benefit of several different in vitro (human primary fibroblasts and hiPSC derived cells) and in vivo (LmnaG609G/G609G KI mice) models, as unique and complementary tools to study these new candidates.

 

Deciphering and elucidate the role of non-coding RNAs in HGPS and other related progeroid syndromes remain a challenge that will help to better understand the pathophysiology of these dramatic diseases, paving the way for new therapeutic proofs of concept.

Principal investigators: Annachiara De Sandre Giovannoli, Ali Badache

 

Hutchinson-Gilford Progeria (HGPS) is a rare, to date incurable, genetic disorder characterized by early and accelerated aging leading to the death of patients around the age of 13. We showed en 2014 that HGPS is due to an autosomal dominant de novo mutation in the LMNA gene resulting in the activation of a cryptic splicing site, which generates the synthesis of an abnormal and toxic nuclear protein, called progerin. This protein accumulates in vivo during patient aging and generates dose-dependent nuclear anomalies, both morphological and functional, such as DNA repair anomalies, deregulation of gene expression, associated with oxidative stress, all of which contribute to the induction of cellular premature senescence.

 

Mandibuloacral dysplasia (MAD) syndromes are rare, mostly autosomal recessive, progeroid disorders with clinical and genetic heterogeneity, characterized by growth

retardation, craniofacial dysmorphic features due to distal bone resorption, musculoskeletal and skin abnormalities associated with lipodystrophy, caused by mutations of the Lamin A/C gene or other genes contributing to Lamin A/C processing and to structure and function of the nuclear lamina. All Lamin-related MAD syndromes, just like HGPS, are characterized by nuclear morphological and functional abnormalities. We recently identified five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia that we called MADaM, for Mandibuloacral dysplasia associated to MTX2 (MDPS; OMIM # 619127), characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. At the cellular level, loss of MTX2 in patient’s primary fibroblasts leads to loss of its membrane partner Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Importantly, patients’ fibroblasts are resistant to induced apoptosis, correlating with increased cell senescence and reduced cell proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans revealing an unsuspected pathophysiological link between mitochondrial composition and function and nuclear morphology.

We wish to deepen our understanding of the pathophysiological basis of MADaM Syndrome and explore its possible links with HGPS and Lamin-related MAD. For that purpose, we have assembled a collection of HGPS and MADaM Syndrome patient-derived fibroblasts, and generated patient-derived induced pluripotent stem cells (iPSCs), that could be differentiated into cell types of relevance for the disease. These, in conjunction with gene-edited iPSCs, constitute unique and precious tools to further explore, through multipronged cellular and molecular approaches, including genomic and epigenomic analyses, the mechanism whereby defects of the mitochondrial proteins MTX2 and MTX1 lead to “HGPS-like” progeroid symptoms. In turn, novel molecular insights should help identify potential therapeutic strategies for MADaM patients.

Principal investigator: Frédérique Magdinier

 

Facio Scapulo Humeral Dystrophy (FSHD) is a peculiar autosomal dominant form of muscular dystrophy with involvement of specific muscles of the face, shoulder and pelvic girdles and peroneal groups, with variable weakness. FSHD is considered as genetically heterogeneous but clinically homogenous with however incomplete penetrance. Two types of FSHD have been described. The first type, FSHD1 is the most frequent and associated with shortening of an array of D4Z4 macrosatellite repeats in the distal 4q35 locus. The second type, FSHD2 (5% of patients) is linked in 80% of cases to mutation in the SMCHD1 gene encoding a chromatin-associated factor which function is poorly understood. This gene is also mutated in an unrelated developmental disorder dubbed Bosma Arhinia and Microphtalmia Syndrome (BAMS). The current and most prevalent molecular model proposed as causative of FSHD associates reduction in the number of D4Z4 repeats (FSHD1) or loss of SMCHD1 function (FSHD2) to hypomethylation of D4Z4, chromatin relaxation and transcription of the most distal copy of the DUX4 gene. However, the molecular mechanisms resulting in the muscle weakness and involved in the muscle specificity are not at all understood.

 

For many years, we have been interested in understanding the regulation of the D4Z4 array and the contribution of epigenetics in FSHD, together with the role of SMCHD1 in this process. Thanks to our unique and close collaboration with the main center for the molecular diagnosis of FSHD in France and the Center of Reference for NMDs, we have access to hundreds of patients’ samples and medical record for clinical research. Over the years, we have developed a large number of tools for in vitro explorations in parallel to in-depth clinical investigations of FSHD patients, including through the development of induced pluripotent stem cells models.

 

Ongoing projects aim at:

o Deciphering the complexity of the 4q35 and homologous 10q26 loci in FSHD patients with atypical genomic features using a combination of genomic approaches including long read sequencing.

o Develop integrative tools for genotype-phenotype correlations in FSHD (collaboration with the systems biomedicine team headed by A. Baudot).

o Defining the contribution of non-muscular cells in the pathogenesis of FSHD. This part of the project includes cutting edge technologies of tissue bioengineering (microfluidics, production of organoids, tissue bioprinting, optogenetics).

o Investigates the dynamics of DNA methylation and the role of SMCHD1 in shaping the epigenome.

Principal investigator: Leslie Caron

 

Leslie Caron’s goal is to better understand the genetic and cellular mechanisms contributing to debilitating skeletal muscle diseases. Her current research is based on modeling neuromuscular disorders using patient’s induced pluripotent stem cells (hiPSC) to contribute to the identification of novel disease-causing genes patients in diagnosis deadlock. To this aim, our team continuously collaborate with hospital services and by combining state-of-the-art molecular and functional technologies (transcriptomics, multi-omics, NGS, calcium imaging and MEA), we are able to identify the genes, biological pathways and functional properties affected in these various neuromuscular diseases. Overall, through stem cells modeling, this project will offer new avenues for understanding muscle pathologies and will facilitate the development of innovative therapeutic approaches.

One of Leslie’s specific focus is also deciphering the pathomechanisms of Laminin a2 deficiency related muscular dystrophy (LAMA2-RD), an ECM-related neuromuscular disorder and one of the most common congenital muscular dystrophies for which there exists no cure.

Principal investigator: Stefano Testa

 

Nowadays there is growing interest in developing alternatives to animal testing for disease modeling. Tissue engineering, thanks to the combination of skills and notions from different disciplines, represents one of the most promising research fields in replicating the morphological and biological complexity typical of human tissues and organs.

In this project, human primary1 and iPS2 cells will be used together with the latest 3D bioprinting technologies3,4 to replicate the biological niche and architecture of skeletal muscle. The goal is to develop mature and functional human skeletal muscles to be used as a reliable platform for studying NMDs.

Starting from cells isolated from healthy donors and patients, pathologies such as FSHD will be modeled and subsequently studied directly on human muscles produced in vitro, offering on the one hand a solid alternative to animal models and on the other a powerful tool for personalized medicine.

 

(1. Testa S. et al., 2020. doi: 10.3389/fphys.2020.553198; 2. Caron L. et al., 2023. doi: 10.3233/JND-230076; 3. Costantini M. et al., 2021. doi: 10.15252/emmm.202012778; 4. Fornetti E. et al., 2023. doi: 10.1088/1758-5090/acb573.)

Mazaleyrat, K.  et al. 2020

Multilineage Differentiation for Formation of Innervated Skeletal Muscle Fibers from Healthy and Diseased Human Pluripotent Stem Cells.

Induced pluripotent stem cells (iPSCs) obtained by reprogramming primary somatic cells have revolutionized the fields of cell biology and disease modeling. However, the number protocols for generating...
Cells - issue: 6 - volume: 9 - pages: 1531.

Mazaleyrat, K.  et al. 2020

Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic...
Int J Mol Sci - issue: 7 - volume: 21 - pages: 2635.

Robin, JD.  et al. 2020

Mitochondrial function in skeletal myofibers is controlled by a TRF2-SIRT3 axis over lifetime.

Telomere shortening follows a developmentally regulated process that leads to replicative senescence of dividing cells. However, whether telomere changes are involved in postmitotic cell function and...
Aging Cell - issue: 3 - volume: 19 - pages: e13097.

Salort-Campana, E.  et al. 2020

Type 1 FSHD with 6-10 Repeated Units: Factors Underlying Severity in Index Cases and Disease Penetrance in Their Relatives Attention.

Molecular defects in type 1 facioscapulohumeral muscular dystrophy (FSHD) are caused by a heterozygous contraction of the D4Z4 repeat array from 1 to 10 repeat units (RUs) on 4q35. This study compared...
int J Mol Sci - issue: 6 - volume: 21 - pages: 2221.

Salsi, V.  et al. 2020

Does DNA Methylation Matter in FSHD?

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4...
Genes - issue: 3 - volume: 11 - pages: 258.

Dion, C.  et al. 2019

SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite

The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for...
Nucleic Acids Res. - issue: 6 - volume: 47 - pages: 2822-2839.

Laberthonnière, C.  et al. 2019

Bring It to an End: Does Telomeres Size Matter?

Telomeres are unique nucleoprotein structures. Found at the edge of each chromosome, their main purpose is to mask DNA ends from the DNA-repair machinery by formation of protective loops. Through life...
Cells - issue: 1 - volume: 8 - pages: .

Sayed, ME.  et al. 2019

NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells

Alternative splicing is dysregulated in cancer cells, driving the production of isoforms that allow tumor cells to survive and continuously proliferate. Part of the reactivation of telomerase involves...
Oncogene - issue: 16 - volume: 38 - pages: 2937-2952.

Roche, S.  et al. 2019

Methylation hotspots evidenced by deep sequencing in patients with facioscapulohumeral dystrophy and mosaicism

Objective: To investigate the distribution of cytosine-guanine dinucleotide (CpG) sites with a variable level of DNA methylation of the D4Z4 macrosatellite element in patients with facioscapulohumeral...
Neurol Genet - issue: 6 - volume: 5 - pages: e372.

Kinoshita, J.  et al. 2019

26th Annual Facioscapulohumeral Dystrophy International Research Congress Marseille, France, 19-20 June 2019


Neuromuscul. Disord. - issue: 10 - volume: 29 - pages: 811-817.

Nguyen, K.  et al. 2019

Deciphering the complexity of the 4q and 10q subtelomeres by molecular combing in healthy individuals and patients with facioscapulohumeral dystrophy

BACKGROUND: Subtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy...
J. Med. Genet. - issue: 9 - volume: 56 - pages: 590-601.

Uboldi, C.  et al. 2019

In Vitro Analysis of the Effects of ITER-Like Tungsten Nanoparticles: Cytotoxicity and Epigenotoxicity in BEAS-2B Cells

Tungsten was chosen as a wall component to interact with the plasma generated by the International Thermonuclear Experimental fusion Reactor (ITER). Nevertheless, during plasma operation tritiated...
Nanomaterials (Basel) - issue: 9 - volume: 9 - pages: .

Francastel, C.  et al. 2019

DNA methylation in satellite repeats disorders

Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of...
Essays Biochem. - issue: - volume: - pages: .

Gaillard, M.  et al. 2019

Analysis of the 4q35 chromatin organization reveals distinct long-range interactions in patients affected with Facio-Scapulo-Humeral Dystrophy

Facio-Scapulo Humeral dystrophy (FSHD) is the third most common myopathy, affecting 1 amongst 10,000 individuals (FSHD1, OMIM #158900). This autosomal dominant pathology is associated in 95% of cases...
Sci Rep - issue: 1 - volume: 9 - pages: 10327.

Nguyen, K.  et al. 2019

Whole Exome Sequencing Reveals a Large Genetic Heterogeneity and Revisits the Causes of Hypertrophic Cardiomyopathy


Circ Genom Precis Med - issue: 5 - volume: 12 - pages: e002500.

Ludlow, AT.  et al. 2018

NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer

Alternative splicing is dysregulated in cancer and the reactivation of telomerase involves the splicing of TERT transcripts to produce full-length (FL) TERT. Knowledge about the splicing factors that...
Nat Commun - issue: 1 - volume: 9 - pages: 3112.

Simoncini, S.  et al. 2017

Biogenesis of Pro-senescent Microparticles by Endothelial Colony Forming Cells from Premature Neonates is driven by SIRT1-Dependent Epigenetic Regulation of MKK6

Senescent cells may exert detrimental effect on microenvironment through the secretion of soluble factors and the release of extracellular vesicles, such as microparticles, key actors in ageing and...
Sci Rep - issue: 1 - volume: 7 - pages: 8277.

Nguyen, K.  et al. 2017

Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy

Facioscapulohumeral dystrophy (FSHD), one of the most common hereditary neuromuscular disorders, is associated with a complex combination of genetic variations at the subtelomeric 4q35 locus. As...
Hum. Mutat. - issue: 10 - volume: 38 - pages: 1432-1441.

Simoncini, S.  et al. 2017

Biogenesis of Pro-senescent Microparticles by Endothelial Colony Forming Cells from Premature Neonates is driven by SIRT1-Dependent Epigenetic Regulation of MKK6

Senescent cells may exert detrimental effect on microenvironment through the secretion of soluble factors and the release of extracellular vesicles, such as microparticles, key actors in ageing and...
Sci Rep - issue: 1 - volume: 7 - pages: 8277.

Robin, JD.  et al. 2016

Physiological and Pathological Aging Affects Chromatin Dynamics, Structure and Function at the Nuclear Edge

Lamins are intermediate filaments that form a complex meshwork at the inner nuclear membrane. Mammalian cells express two types of Lamins, Lamins A/C and Lamins B, encoded by three different genes,...
Front Genet - issue: - volume: 7 - pages: 153.

Kim, W.  et al. 2016

Regulation of the Human Telomerase Gene TERT by Telomere Position Effect-Over Long Distances (TPE-OLD): Implications for Aging and Cancer

Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short...
PLoS Biol. - issue: 12 - volume: 14 - pages: e2000016.

Gaillard, M.  et al. 2016

Segregation between SMCHD1 mutation, D4Z4 hypomethylation and Facio-Scapulo-Humeral Dystrophy: a case report

BACKGROUND: The main form of Facio-Scapulo-Humeral muscular Dystrophy is linked to copy number reduction of the 4q D4Z4 macrosatellite (FSHD1). In 5 % of cases, FSHD phenotype appears in the absence...
BMC Med. Genet. - issue: 1 - volume: 17 - pages: 66.

Chateau, A.  et al. 2016

SIRT1 Deficiency in endothelial progenitor cells drives pro-senescent microparticles release through MKK6 upregulation

WOS:000379164000355
J. Thromb. Haemost. - issue: - volume: 14 - pages: 139-139.

Lecocq, C.  et al. 2016

Delayed-onset Friedreich's ataxia revisited

BackgroundFriedreich's ataxia usually occurs before the age of 25. Rare variants have been described, such as late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, occurring after 25...
Mov. Disord. - issue: 1 - volume: 31 - pages: 62-69.

Portilho, DM.  et al. 2015

miRNA expression in control and FSHD fetal human muscle biopsies

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder and is one of the most common forms of muscular dystrophy. We have recently shown that some hallmarks of...
PLoS ONE - issue: 2 - volume: 10 - pages: e0116853.

Robin, JD.  et al. 2015

SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can...
Genome Res. - issue: 12 - volume: 25 - pages: 1781-1790.

Pilliod, J.  et al. 2015

New Practical Definitions for the Diagnosis of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Objective: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the...
Ann. Neurol. - issue: 6 - volume: 78 - pages: 871-886.

Boushaki, S.  et al. 2015

Prevalence of BTK mutations in male Algerian patterns with agammaglobulinemia and severe B cell lymphopenia

X linked agammaglobulinemia (XLA) is the first described primary immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent infections,...
Clin. Immunol. - issue: 2 - volume: 161 - pages: 286-290.

Robin, JD.  et al. 2015

SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can...
Genome Res. - issue: 12 - volume: 25 - pages: 1781-1790.

Boushaki, S.  et al. 2015

Prevalence of BTK mutations in male Algerian patterns with agammaglobulinemia and severe B cell lymphopenia

X linked agammaglobulinemia (XLA) is the first described primary immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent infections,...
Clin. Immunol. - issue: 2 - volume: 161 - pages: 286-290.

Mariot, V.  et al. 2015

Correlation between low FAT1 expression and early affected muscle in FSHD

WOS:000362925400444
Neuromusc. Disord. - issue: - volume: 25 - pages: S312-S312.

Mariot, V.  et al. 2015

Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy

OBJECTIVE: Facioscapulohumeral muscular dystrophy (FSHD) is linked to either contraction of D4Z4 repeats on chromosome 4 or to mutations in the SMCHD1 gene, both of which result in the aberrant...
Ann. Neurol. - issue: 3 - volume: 78 - pages: 387-400.

Nguyen, K.  et al. 2015

Incidental findings on array comparative genomic hybridization: detection of carrier females of dystrophinopathy without any family history

Array comparative genomic hybridization (aCGH) has progressively replaced conventional karyotype in the diagnostic strategy of intellectual disability (ID) and congenital malformations. This technique...
Clin. Genet. - issue: 5 - volume: 87 - pages: 488-491.

Puppo, F.  et al. 2015

Identification of variants in the 4q35 gene FAT1 in patients with a facioscapulohumeral dystrophy-like phenotype

Facioscapulohumeralmuscular dystrophy (FSHD) is linked to copy-number reduction (N < 10) of the 4q D4Z4 subtelomeric array, in association with DUX4-permissive haplotypes. This main form is indicated...
Hum. Mutat. - issue: 4 - volume: 36 - pages: 443-453.

Portilho, DM.  et al. 2015

miRNA Expression in Control and FSHD Fetal Human Muscle Biopsies

Background Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder and is one of the most common forms of muscular dystrophy. We have recently shown that some hallmarks of FSHD...
PLoS One - issue: 2 - volume: 10 - pages: e0116853.

Salort-Campana, E.  et al. 2015

Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study

BACKGROUND: Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35....
Orphanet J Rare Dis - issue: - volume: 10 - pages: 2.

Badja, C.  et al. 2014

Efficient and Cost-Effective Generation of Mature Neurons From Human Induced Pluripotent Stem Cells

For years, our ability to study pathological changes in neurological diseases has been hampered by the lack of relevant models until the recent groundbreaking work from Yamanaka's group showing that...
Stem Cells Transl. Med. - issue: 12 - volume: 3 - pages: 1467-1472.

Badja, C.  et al. 2014

Efficient and cost-effective generation of mature neurons from human induced pluripotent stem cells

For years, our ability to study pathological changes in neurological diseases has been hampered by the lack of relevant models until the recent groundbreaking work from Yamanaka's group showing that...
Stem Cells Transl Med - issue: 12 - volume: 3 - pages: 1467-1472.

Robin, JD.  et al. 2014

Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor...
Genes Dev. - issue: 22 - volume: 28 - pages: 2464-2476.

Robin, JD.  et al. 2014

Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor...
Genes Dev. - issue: 22 - volume: 28 - pages: 2464-2476.

Gaillard, M.  et al. 2014

Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers

OBJECTIVE: We investigated the link between DNA hypomethylation and clinical penetrance in facioscapulohumeral dystrophy (FSHD) because hypomethylation is moderate and heterogeneous in patients and...
Neurology - issue: 8 - volume: 83 - pages: 733-742.

Vassallo, PF.  et al. 2014

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic...
Blood - issue: 13 - volume: 123 - pages: 2116-2126.

Vassallo, PF.  et al. 2014

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic...
Blood - issue: 13 - volume: 123 - pages: 2116-2126.

Ferreboeuf, M.  et al. 2014

DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first...
Hum. Mol. Genet. - issue: 1 - volume: 23 - pages: 171-181.

Poulain, S.  et al. 2013

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

SNP array (SNPa) was developed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) without copy number changes, CN-LOH. We aimed to identify novel genomic aberrations using SNPa in...
Am. J. Hematol. - issue: 11 - volume: 88 - pages: 948-954.

Broucqsault, N.  et al. 2013

Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy

Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is...
Hum. Mol. Genet. - issue: 20 - volume: 22 - pages: 4206-4214.

Robin, JD.  et al. 2013

Length dependent telomere looping affects long-distant gene expression (5 Mb) in FSHD

WOS:000324972500271
Neuromusc. Disord. - issue: 9-10 - volume: 23 - pages: 824-824.

Ferreboeuf, M.  et al. 2013

DUX 4 and DUX4 downstream target genes are expressed in fetal FSHD muscles

WOS:000324972500267
Neuromusc. Disord. - issue: 9-10 - volume: 23 - pages: 823-823.

Boussouar, A.  et al. 2013

Acacetin and chrysin, two polyphenolic compounds, alleviate telomeric position effect in human cells

We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE) to design a high-throughput screening assay for drugs altering telomeres. We...
Mol Ther Nucleic Acids - issue: - volume: 2 - pages: e116.

Boussouar, A.  et al. 2013

Acacetin and Chrysin, Two Polyphenolic Compounds, Alleviate Telomeric Position Effect in Human Cells

We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE) to design a high-throughput screening assay for drugs altering telomeres. We...
Mol. Ther.-Nucl. Acids - issue: - volume: 2 - pages: e116.

Caruso, N.  et al. 2013

Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy

Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts....
PLoS Genet. - issue: 6 - volume: 9 - pages: e1003550.

Diala, I.  et al. 2013

Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway

The DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/beta-catenin signalling pathway in...
EMBO Rep. - issue: 4 - volume: 14 - pages: 356-363.

Diala, I.  et al. 2013

Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway

The DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/β-catenin signalling pathway in human...
EMBO Rep. - issue: 4 - volume: 14 - pages: 356-363.

Roche, S.  et al. 2013

Comparative analysis of protein expression of three stem cell populations: Models of cytokine delivery system in vivo

Several mechanisms mediate the regenerative and reparative capacity of stem cells, including cytokine secretion; therefore these cells can act as delivery systems of therapeutic molecules. Here we...
Int. J. Pharm. - issue: 1 - volume: 440 - pages: 72-82.

Galati, A.  et al. 2012

TRF2 controls telomeric nucleosome organization in a cell cycle phase-dependent manner

Mammalian telomeres stabilize chromosome ends as a result of their assembly into a peculiar form of chromatin comprising a complex of non-histone proteins named shelterin. TRF2, one of the shelterin...
PLoS ONE - issue: 4 - volume: 7 - pages: e34386.

Herbaux, C.  et al. 2012

B-Cell-Specific Transcription Factor BACH2 Involved in the Clinical Behavior Heterogeneity of Waldenstrom Macroglobulinemia

WOS:000313838902278
Blood - issue: 21 - volume: 120 - pages: .

Fahiminiya, S.  et al. 2012

Improvement of 2D-PAGE Resolution of Human, Porcine and Canine Follicular Fluid: Comparison of Two Immunodepletion Columns

Contents Follicular fluid provides the microenvironment within which somatic cells proliferate and differentiate, and the oocyte matures. It contains a number of soluble factors implicated in various...
Reprod. Domest. Anim. - issue: 5 - volume: 47 - pages: e67-e70.

Galati, A.  et al. 2012

TRF2 Controls Telomeric Nucleosome Organization in a Cell Cycle Phase-Dependent Manner

Mammalian telomeres stabilize chromosome ends as a result of their assembly into a peculiar form of chromatin comprising a complex of non-histone proteins named shelterin. TRF2, one of the shelterin...
PLoS One - issue: 4 - volume: 7 - pages: e34386.

Simonet, T.  et al. 2011

The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats

The study of the proteins that bind to telomeric DNA in mammals has provided a deep understanding of the mechanisms involved in chromosome-end protection. However, very little is known on the binding...
Cell Res. - issue: 7 - volume: 21 - pages: 1028-1038.

Ye, J.  et al. 2010

TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage

Human telomeres are protected from DNA damage by a nucleoprotein complex that includes the repeat-binding factor TRF2. Here, we report that TRF2 regulates the 5' exonuclease activity of its binding...
Cell - issue: 2 - volume: 142 - pages: 230-242.

Falandry, C.  et al. 2010

CLLD8/KMT1F is a lysine methyltransferase that is important for chromosome segregation

Proteins bearing a SET domain have been shown to methylate lysine residues in histones and contribute to chromatin architecture. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an...
J. Biol. Chem. - issue: 26 - volume: 285 - pages: 20234-20241.

Ourliac-Garnier, I.  et al. 2010

Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1

Telomeres, the nucleoprotein complexes located at the ends of chromosomes, are involved in chromosome protection and genome stability. Telomeric repeat binding factor 1 (TRF1) and telomeric repeat...
J. Biol. Inorg. Chem. - issue: 5 - volume: 15 - pages: 641-654.

Arnoult, N.  et al. 2010

Replication timing of human telomeres is chromosome arm-specific, influenced by subtelomeric structures and connected to nuclear localization

The mechanisms governing telomere replication in humans are still poorly understood. To fill this gap, we investigated the timing of replication of single telomeres in human cells. Using in situ...
PLoS Genet. - issue: 4 - volume: 6 - pages: e1000920.

Ottaviani, A.  et al. 2010

D4Z4 as a prototype of CTCF and lamins-dependent insulator in human cells

Using cellular models that mimic the organizations of the subtelomeric 4q35 locus found in patients affected with Facio-Scapulo-Humeral Dystrophy (FSHD) and in healthy individuals, we recently...
Nucleus - issue: 1 - volume: 1 - pages: 30-36.

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